Guidelines for the use of nonoccupational postexposure prophylaxis (NPEP) have been released in many countries [1–3]. In Australia, guidelines recommending use after high-risk sexual and percutaneous exposures were introduced in New South Wales in 1998  and extended nationally in 2001 [5,6]. The notion that postexposure prophylaxis (PEP) after sexual exposure may prevent HIV infection is based on preclinical studies on animals [7,8], prospective studies of postpartum antiretroviral use to prevent mother-to-child transmission [9–11] and observational data on PEP use in occupational settings . There have been no randomized trials of NPEP after sexual exposure, but observational data do suggest some efficacy . In a review of 2086 potential sexual or injection drug exposures to HIV, five cases of HIV seroconversion due to NPEP failure were reported . In Australia, no cases of NPEP failure in fully adherent participants were identified in a clinical cohort of 1552 individuals who received NPEP .
Although there have been several large clinic-based series of people receiving NPEP, there are few prospective data on the use of NPEP in the community . In this review, we present data from a large prospective cohort of HIV-negative homosexual men recruited from a wide range of community settings in Sydney and followed for up to 6 years. We explore the awareness of the availability of NPEP and factors that predicted NPEP use, the relationship between NPEP use and future HIV risk behaviours and HIV infection in this cohort of men.
The Health in Men (HIM) study was a community-based prospective cohort study of HIV-negative homosexually active men in Sydney. The methodology for the HIM study has been published previously . The study recruited participants from June 2001 to December 2004 and concluded interviews in June 2007. Written informed consent was obtained from all potential study participants prior to enrolment. Men who were 18 years or older, tested HIV-negative, had sexual contact with at least one man in the past 5 years, lived in Sydney or had regular contact with gay events and venues in Sydney were eligible to enrol. The HIM study received ethics approval from the University of New South Wales.
All participants underwent annual structured face-to-face interviews on a wide range of topics, including sexual relationships and practices, injecting drug use and use of NPEP. Serological testing for HIV testing was performed annually using a combined antigen–antibody test (AxSYM, HIV Antigen–Antibody Combo, Abbott Diagnostics, Abbott Park, Illinois, USA). At approximately 6 months between annual face-to-face interviews, information on recent sexual relationships and practices and injecting drug use was collected via a short-version telephone interview.
Quantitative sexual behaviour data were collected. Details were recorded of the number of episodes of unprotected insertive and receptive anal sexual intercourse for each participant at baseline and then every 6 months. Data were collected separately by partner type (regular or casual), by partner's HIV status (HIV positive, HIV negative or of unknown HIV status), by sexual position (insertive or receptive) and for receptive anal intercourse, by whether ejaculation occurred inside the rectum.
Four questions on NPEP use were asked at the baseline interview. These were whether the participant had heard of NPEP, had ever taken NPEP, how many times if they had taken NPEP and who prescribed or provided the NPEP. These questions were repeated annually. From 2003 onwards, an additional question was asked on when the participant last received NPEP (categorized as less than a week, 1–4 weeks ago, 1–3 months ago, 4–6 months ago and 7–12 months ago). There was no education about NPEP provided in the study, and participants who accessed NPEP did so through means available to the wider gay community in Sydney. No data on antiretroviral drugs prescribed as NPEP or adherence to NPEP were collected.
Incident HIV infections were identified through two sources. First, HIV diagnoses at the annual study visit were identified. Second, for consenting participants, identifiers from the HIM study were matched against the national HIV register to identify HIV infections that occurred in people who tested outside the study. The final match against the national HIV register, and the final study interviews, occurred in June 2007 .
Statistical analysis was performed using STATA 10.0 (STATA Corporation, College Station, Texas, USA).
Incident nonoccupational postexposure prophylaxis use
Incident NPEP use was ascertained from participant report of NPEP use at the annual face-to-face interviews. Incident NPEP use was calculated as the number of episodes of NPEP divided by the total person-years followed. Potential demographic and behavioural predictors of incident NPEP use were analysed by univariate and multivariate Cox regression models. As multiple uses of NPEP by the same participant during the study period were possible, models were used that allowed for repeated measures in the same individual. These models, which allow for within and between-participant variability, provide robust variance estimates, and therefore, appropriate P values and confidence intervals (CIs) . The trend for the incidence of NPEP use by calendar year during the course of the study was calculated using Cox regression.
Behaviour change after nonoccupational postexposure prophylaxis use
Change in HIV risk behaviour after NPEP use was measured by the difference between the number of acts of unprotected anal intercourse (UAI) with HIV-positive or status-unknown partners (hereafter called ‘nonconcordant UAI’) in the 6 months prior to NPEP and first, the number of nonconcordant UAI acts in the 6 months after NPEP and second, the number of nonconcordant UAI acts in the 18 months after NPEP. As NPEP is generally prescribed after a high-risk episode, the 6-month period in which the risk episode leading to NPEP prescription occurred was excluded from this calculation. The change in the number of nonconcordant UAI acts before and after NPEP was examined using the Wilcoxon signed-rank test. Men who reported NPEP use at the exit interview were excluded from the analysis of change in UAI acts, as 6-month data after NPEP use were not available.
For HIV incidence and risk factor analysis, total person-years were calculated as the time from study entry to the estimated date of HIV seroconversion. For participants who remained HIV negative, this was to June 2007 in participants who consented to matching, or to the date of their last interview in those few who did not consent to matching. The exact binomial method was used to calculate 95% CIs.
Nonoccupational postexposure prophylaxis use and subsequent HIV seroconversion
The relationship between NPEP use and subsequent HIV seroconversion was analysed by determining the relative risk of HIV infection in men who received NPEP compared with those who did not receive NPEP, using Cox regression. Multivariate models examining the association of NPEP use with HIV seroconversion were adjusted for the report of UAI with HIV-negative, HIV status unknown and HIV-positive partners.
From June 2001 to December 2004, a total of 1427 participants were enrolled in the HIM study. The median age at enrolment was 35 years (range 18–75). The majority (95.2%) of participants self identified as gay or homosexual. By the end of the HIM study in June 2007, the total follow-up time was 4537.8 person-years, and median follow-up was 3.9 years. At baseline, 78.5% of participants had heard of NPEP, and 6.3% reported receiving NPEP previously. By the fifth annual interview, 97.4% of participants had heard of NPEP, and 220 (15.4%) had ever received it. Of those who had received NPEP at baseline, the majority (89%) had received NPEP only once before.
Incident nonoccupational postexposure prophylaxis use
One hundred and fifty-four participants reported 196 incident uses of NPEP during the study period (4.36 per 100 person-years, 95% CI 3.78–5.00), with 24 men (16%) reporting NPEP use on two occasions, and nine men (6%) reporting NPEP use on three occasions. Demographic predictors of incident NPEP use included younger age (P trend = 0.001) and a higher level of education (P trend = 0.015). Those who reported use of NPEP at study enrolment were much more likely to report incident NPEP use (P < 0.001) (Table 1). UAI in the past 6 months was a strong behavioural predictor of use of NPEP during the study, and incidence of NPEP use was consistently higher among those who reported higher levels of sexual risk behaviour. Incident NPEP use approached one in five participants per year among those who reported the highest risk behaviours (receptive UAI with ejaculation with casual partners and UAI with HIV-positive casual partners) (Table 2). Overall, 82% of incident uses of NPEP were during a risk period in which UAI was reported. When data were further stratified by sexual position in UAI with HIV-positive partners, one in five participants per year who reported receptive UAI with ejaculation in the rectum with regular HIV-positive partners (19.69 per 100 person-years) and one in two participants per year who reported receptive UAI with ejaculation with HIV-positive casual partners reported NPEP use (48.98 per 100 person-years).
In the multivariate analysis, incident NPEP use remained significantly associated with younger age (hazard ratio 0.74, 95% CI 0.63–0.87, P trend < 0.001), previous NPEP use at study enrolment (hazard ratio 2.37, 95% CI 1.60–3.53, P < 0.001), higher levels of education (hazard ratio 1.18, 95% CI 1.04–1.34, P trend = 0.01) and reported UAI with casual partners by HIV status (hazard ratio 1.92, 95% CI 1.72–2.14, P trend < 0.001).
During follow-up, NPEP use increased significantly from 2.9 per 100 person-years in 2002 to 7.1 per 100 person-years in 2007 (P = 0.007) (Fig. 1). During the study, there was a significant increase in the number of men reporting NPEP use who reported no UAI exposures in the past 6 months (P = 0.04). However, it should be noted that apart from a peak of 3.75 per 100 person-years incident use in 2006, use in this low-risk group remained less than 2.0 per 100 person-years during the study period.
Behaviour change after nonoccupational postexposure prophylaxis use
Behavioural data before and 6 months after NPEP use were available for 154 incident reports of NPEP use. For the remaining 42, NPEP use was reported at the exit interview, and thus, no post-NPEP behavioural data were available. There was no significant increase or decrease in nonconcordant UAI overall, or in any category of UAI, by sexual position or by partner's HIV status, after NPEP use (Table 3). For 89 incident reports of NPEP use, behavioural data were available for at least 18 months after the NPEP use period. There was no significant change in HIV risk behaviour after NPEP use in this time period (data not shown).
Nonoccupational postexposure prophylaxis use and subsequent HIV seroconversion
By the end of the HIM study, there were 53 HIV seroconversions identified, giving an overall HIV incidence of 0.78 per 100 person-years (95% CI 0.59–1.02). The median age at HIV seroconversion was 37 years (range 22–63). Men who had previously received NPEP had an almost three-fold higher rate of HIV seroconversion subsequently (hazard ratio 2.67, 95% CI 1.40–5.08, P = 0.003). However, this was no longer significant after adjusting for sexual risk behaviour (hazard ratio 1.70, 95% CI 0.87–3.34, P = 0.123).
In this community-based cohort of homosexual men in Australia, awareness of the availability of NPEP was nearly universal. NPEP use increased rapidly from 2 to 7% of men each year over the life of the study. NPEP was used mostly by men who reported high-risk behaviours but was not associated with reductions in risk behaviour. Consequently, use was a significant predictor of future HIV infection. Thus, although NPEP use is likely to have averted HIV infections associated with specific exposures, NPEP did not reduce long-term risk of HIV infection in these high-risk individuals.
Knowledge of NPEP among HIM participants was very high (78.5% at baseline and 97.4% of participants by the final study year) compared with other studies. In a survey of 1819 HIV-uninfected gay/bisexual men in California conducted in 2006, 47% reported PEP awareness , and among male attendees of Minority Gay Pride Events in seven US cities in 2005 and 2006, only 21% had heard of people taking antiretrovirals to prevent HIV infection . The higher awareness of NPEP among Sydney gay men is probably related to targeted publicity campaigns and wide promotion of NPEP since 1999.
Younger men, men with a tertiary education and men who reported NPEP use at study enrolment were more likely to use NPEP during the study. Uptake of NPEP was very high in men reporting the highest risk behaviours, and the majority of reported NPEP use seemed clinically appropriate. Over 80% of use was during a period in which UAI was reported, and the incidence of NPEP use was less than 2% in men who reported no UAI in the past 6 months. In contrast, it was 20% or more for those who reported the highest risk anal sex behaviours. No one reported NPEP use more than three times, and only one in five of those who used NPEP used it more than once.
If NPEP is to have a significant population-level effect on HIV incidence, then it must be used after a substantial proportion of risk episodes. In the HIM study, over the 5-year study period involving 1427 participants, there were 1782 6-month periods in which nonconcordant UAI was reported. NPEP was used during 116 (6.5%) of these risk periods. This represents a small proportion of eligible exposures during the study period. A similar finding was seen in an intervention study on homosexual men in Brazil where NPEP starter packs were provided at baseline. In that study, only 57% of men who reported a high-risk exposure used NPEP, even though they had ready access to it . Thus, even though NPEP use increased significantly during the study period, and almost all HIM participants were aware of its availability, there was little evidence of overuse of NPEP in this population. After many risk episodes, participants may have underestimated their HIV risk  or accepted their level of HIV risk and did not seek NPEP . This raises the important question, which cannot be answered by this research, of why participants used NPEP for that particular occasion of risk but not for subsequent reported risk episodes.
The impact of NPEP on HIV risk behaviour has been investigated in observational studies in other countries. These have shown that NPEP use does not result in increased risk behaviour, particularly when combined with behavioural counselling [16,23]. The Brazilian study referred to above reported a decline in high-risk sexual activities among both NPEP users and nonusers who had access to NPEP starter packs . Among 397 people prescribed NPEP between 1997 and 1999 in San Francisco, there was a marked decrease in high-risk acts with high-risk partners in the 6–12 months after NPEP use. However, in that study, subsequent HIV risk behaviour was compared with risk behaviour in the 3 months prior to NPEP prescription, which included the risk episode leading to NPEP, and hence, the reduction in risk may simply represent regression to the mean . The largest dispenser of NPEP in Sydney is a hospital that is adjacent to the HIM study interview location and provides NPEP with routine adjunctive risk reduction counselling . Thus, it is likely that many NPEP recipients in HIM received behavioural counselling. Given this, the fact that we found no change in sexual behaviour 6 months after 154 incident NPEP uses and after at least 18 months for 89 incident NPEP uses is somewhat disappointing.
Prior NPEP users were around three times more likely to seroconvert to HIV, but this was explained by a higher prevalence of nonconcordant UAI among NPEP users. The higher risk of subsequent HIV seroconversion among men who reported NPEP use is unlikely to indicate NPEP failure but rather seroconversion related to risk episodes after NPEP completion.
This study had the strength of being a large-scale prospective cohort study. The sample was primarily community based, and we believe that it can be considered as broadly representative of gay HIV-negative men in Sydney. Participant identifiers were matched with the national HIV register to capture HIV seroconversions that may not have been detected in the HIM study. This method prevented any substantial underestimation of HIV incidence in this cohort due to loss to follow-up .
There were several important limitations in this study, including reliance on participants' self-report to measure NPEP use, which was not validated using clinical records. NPEP use was categorized into two time periods, 1 week to 6 months and 7 months to 1 year prior to interview. Potentially, this time range may have diluted the evidence of an immediate decrease in HIV risk behaviour. However, even if this was accurate, there is no evidence of a sustained effect of NPEP use on participants' HIV risk behaviour. In addition, this relatively wide time interval and the fact that we did not have data on adherence to NPEP meant we were not able to conclude with certainty whether any of the HIV infections after NPEP use were related to NPEP failure. Nevertheless, these results are consistent with the absence of HIV seroconversions in recent Australian NPEP studies [15,25].
This study clearly paints a picture of increasing and mainly appropriate use of NPEP among homosexual men in Sydney, Australia. The highest incidence of NPEP use was reported after the highest risk behaviours. However, there was no evidence of a long-term effect of NPEP on decreasing either HIV risk behaviour or HIV incidence. These data suggest that the current design of NPEP programmes needs to be reconsidered and indicate that if NPEP is to result in a decrease in personal HIV risk, then long-term targeted prevention interventions will be required in individuals who receive NPEP.
The authors thank all participants, the dedicated HIM study team and the participating doctors and clinics.
The National Centre in HIV Epidemiology and Clinical Research and the National Centre in HIV Social Research are funded by the Australian Government Department of Health and Ageing. The Health in Men cohort study was funded by the National Institutes of Health, a component of the US Department of Health and Human Services (NIH/NIAID/DAIDS: HVDDT Award N01-AI-05395), the National Health and Medical Research Council in Australia (project grant #400944), the Australian Government Department of Health and Ageing (Canberra) and the New South Wales Health Department (Sydney). I. Mary Poynten is funded by a National Health and Medical Research Council Public Health Postgraduate scholarship.
All authors (I. Mary Poynten, Fengyi Jin, Limin Mao, Garrett P. Prestage, Susan C. Kippax, John M. Kaldor, John Imrie and Andrew E. Grulich) contributed to the design of the study and the development and critical revision of the manuscript. I. Mary Poynten formulated and performed the statistical analysis and interpreted the data. Fengyi Jin and Limin Mao were involved in the analysis and interpretation of the data. Andrew E. Grulich took overall responsibility for the project and provided epidemiological expertise. I. Mary Poynten drafted the manuscript, to which all authors contributed. All authors have seen and approved the final version of the manuscript.
There are no conflicts of interest.
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